title: Calcium-dependent N-cadherin up-regulation mediates reactive astrogliosis and neuroprotection after brain injury.
abstract: Brain injury induces phenotypic changes in astrocytes, known as reactive astrogliosis, which may influence neuronal survival. Here we show that brain injury induces inositol 1,4,5-trisphosphate (IP3)-dependent Ca(2+) signaling in astrocytes, and that the Ca(2+) signaling is required for astrogliosis. We found that type 2 IP3 receptor knockout (IP3R2KO) mice deficient in astrocytic Ca(2+) signaling have impaired reactive astrogliosis and increased injury-associated neuronal death. We identified N-cadherin and pumilio 2 (Pum2) as downstream signaling molecules, and found that brain injury induces up-regulation of N-cadherin around the injured site. This effect is mediated by Ca(2+)-dependent down-regulation of Pum2, which in turn attenuates Pum2-dependent translational repression of N-cadherin. Furthermore, we show that astrocyte-specific knockout of N-cadherin results in impairment of astrogliosis and neuroprotection. Thus, astrocytic Ca(2+) signaling and the downstream function of N-cadherin play indispensable roles in the cellular responses to brain injury. These findings define a previously unreported signaling axis required for reactive astrogliosis and neuroprotection following brain injury.
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kanemaru
authors.forename: Jun
authors.initials: J
authors.lastname: Kubota
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sekiya
authors.forename: Kenzo
authors.initials: K
authors.lastname: Hirose
authors.forename: Yohei
authors.initials: Y
authors.lastname: Okubo
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Iino
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D001930:Brain Injuries / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D015820:Cadherins / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D015820:Cadherins; D002118:Calcium
keywords: calcium signal; reactive astrocyte; stab wound; translational repressor